The Future of Clinical Trials

Transcription

1 The Future of Clinical Trials 28 January 2013, European Parliament, Brussels Hosted by Rebecca Taylor MEP Executive Summary The Future of Clinical Trials brought clinical and regulatory experts together with policymakers and patient organisations to discuss developments in clinical trials over the next two decades the impacts of scientific and societal change and the question of whether the proposed Clinical Trials Regulation is adequately prepared to meet the regulatory challenges that these developments might pose. Numerous transitions are underway in the field of clinical research. Our understanding of disease is gradually shifting from a symptomatic to a molecular basis. Developments in regenerative medicine are leading to advanced therapies (gene, tissue and cell) now starting to reach patients. Meanwhile, trial recruitment is evolving, whether by access to information on virtual trials via the internet, or biomarker screening platforms that can match patients to trials rather than relying on traditional recruitment via investigators. With increasing ability to collect and share data, clinical trials increasingly coexist with real world data, leading to future possibilities for adaptive licensing, where the development pathway is specific for each medicine. Patient expectations are also changing: in the future, data from trials can be returned to patients and integrated into their electronic medical records. Trials will thus be less isolated from patients normal care environments. There was acknowledgement that the 2001 Clinical Trials Directive has contributed to a decline in the number of clinical trials conducted in Europe. The Commission s proposed Regulation was welcomed for its aims to raise research standards and make Europe more welcoming for medical innovation and international cooperation. Yet there is room for improvement to ensure the Regulation is fully effective in regulating trials as they change. Amidst a wide-ranging discussion, participants argued that: Increased patient engagement and the introduction of risk-based assessments were welcome, as was the proposal s contribution to transparency of trial conduct and results though there may be room for improvements in the area of rare diseases. The role of ethics committees needs to be clarified, but the proposed assessment timelines, which have been benchmarked against international best practice, should be maintained. This is essential to enhance the attractiveness of the EU for clinical research, and to allow patients early access to treatments. Regulatory change may be needed nationally, but this should not be shied away from. With many future developments in clinical research unknown, a review clause should be introduced to future proof the legislation. The Clinical Trials Regulation should also be seen in the wider regulatory context: for example, in discussions on the Data Protection Regulation, necessary exceptions for health research may be endangered. 1

2 Meeting Report On 28 January 2013, Rebecca Taylor MEP (ALDE, UK) hosted a debate on The Future of Clinical Trials in the European Parliament. The debate was organised by Pfizer and the European Association for Bio-industries (EuropaBio). Aim Biomedical science is developing fast, and society s expectations of medicine and research are changing too. Clinical trials therefore also change, putting scientific developments into practice and reflecting the world that patients live in. Testing more targeted therapies, the advent of virtual trials, and increased patient engagement are just some examples of these developments. With the proposed Clinical Trials Regulation planned to be implemented in 2016, The Future of Clinical Trials provided participants with an opportunity to discuss how trials may develop over the next decade, and to reflect on how the Regulation can best deal with such changes and support medical excellence and innovation in the EU. Participants The event was attended by a large range of representatives from the EU and Switzerland, including officials from the Commission s Directorates-General Health & Consumer (SANCO), Research, and Environment; attachés from several EU member state permanent representations; officials from the European Parliament and MEP assistants; academics and representatives from the pharmaceutical industry. Speakers presentations and the full list of participants are available on request from [email protected]. Introduction The host of the event, Rebecca Taylor MEP (ALDE, UK), opened the discussion by highlighting to the audience the many challenges clinical research faces. The drug development community is dealing with a decline in blockbuster drugs used by large populations, but an increase in personalised therapies that require clinical trials targeted at more specific populations, which can be harder to find. Ms Taylor also raised the issue of the development of regenerative medicine which provides potential innovative cures but in some cases is subject to ethical debate. This can be addressed: trials for gene therapies are now well established, for example. Meanwhile, long term advances in computer modelling may reduce but not eliminate the need for clinical trials. With regard to the revision of the current clinical trials legislation, Ms Taylor reminded the audience that stakeholders acknowledge that the 2001 Clinical Trials Directive had contributed to the decrease in the number of clinical trials conducted in Europe. She noted that the proposal for a Clinical Trials Regulation from the Commission has therefore been warmly welcomed, but that some issues are subject to further discussion, including assessment timelines, the role of ethics committees, and clinical data transparency. 2

3 Overview of the proposed Clinical Trials Regulation Stefano Soro, Head of Unit, Medicinal products quality, safety and efficacy Unit, DG Sanco, European Commission Mr Soro provided an overview of the Commission s proposal to replace the current Clinical Trials Directive with a new Regulation. He opened by stating that although the current Directive provides high standards of patient protection that should be preserved and further enhanced, it has created difficulties for sponsors, in particular non-commercial ones, as well as for conducting international clinical trials. More specifically, the current Directive led to an increase in administrative costs, insurance fees, and delays: time to trial launch has increased by 90% 1. Other factors influencing the 25% reduction in the applications for clinical trials in Europe between 2007 and 2011 have included the venture capital environment, the financial crisis, and growing global competition for clinical trial placement. Nevertheless, the EU should address those aspects it has control over. Mr Soro highlighted a number of key features of the proposed Regulation: Streamlining of the application: o The new text will provide for a centralised application process, with the creation of a unique electronic portal for the registration of every clinical trial, a single process for clinical trials applications, the designation of a single national contact point, and the creation of a single clinical trials database. No trial can start if not applied for and authorised through the portal. o The proposed assessment timelines are based on the performance of the most efficient EU member states and third countries. o There will be a single authorisation per Member State that will take into account ethical concerns. The proposal complies with the principles for applications described in paragraphs 14 and 15 of the Declaration of Helsinki. Mr Soro stressed that ethics committee assessment is clearly required in the proposal. The risk-adaptation of clinical trials: o The creation of low-interventional clinical trials creates swifter procedures for clinical trials that pose minimal risk to the subject and thus reduce administrative burden for both the sponsor and the regulator. Transparency of clinical trials data: o The proposal includes stricter provisions for the publication of results. A single, public, mandatory clinical trials database containing a summary of data from each clinical trial will enhance transparency standards. However, Mr Soro noted that recent debate on clinical trials data is more closely related to how medicines are authorised. A process to define the parameters of release of clinical data for authorised products is currently underway at the 1 COM(2012) 369 final, p.3 3

4 European Medicines Agency, which should be considered separately from provisions under clinical trials legislation. The Commission supports EMA's transparency policy. What does the future hold for clinical trials? Case studies and emerging trends. In this session, speakers provided a brief overview on specific innovative issues surrounding clinical trials. The horizon for advanced therapies Dr Rob Janssen, Alliance for Advanced Therapies Dr Janssen provided a brief introduction to the Alliance for Advanced Therapies and proceeded to showcase the clinical potential of advanced therapies. These therapies are different from traditional drugs, because they can have a positive, long-term health effect on patients with one treatment. Advanced therapies may even offer real cures in the future. Many advanced therapies under development are particularly relevant in the context of ageing populations. He outlined the various types of advanced therapies, including gene therapy, cell therapy, and tissue engineering, with the latter already resulting in medicinal products which have been placed on the market. He presented two key messages: Advanced therapies are not as new as people may think. A large body of knowledge and experience with these therapies has been built over the last twenty years. As an example: since 2000 over 10,000 patients have been treated in gene therapy trials in the EU and US without safety issues. Because of this existing knowledge and support from the EMA s Committee for Advanced Therapies, there is no need for longer assessment timelines for clinical trials with Advanced Therapy Medicinal Products. Dr Janssen argued that the Clinical Trials Regulation must support the development of advanced therapies through the creation of a suitable regulatory framework. Trial challenges for stem cell therapies Lydia Dorrego, Clinical Operations Director, TiGenix The Belgium-based biotech company TiGenix developed the first authorised cell therapy in Europe. Ms Dorrego presented a case study on the ongoing development of one of TiGenix s stem-cell therapy products (Cx601) based on expanded allogenic adipose-derived stem cells (easc) 2, which was identified as having therapeutic potential for inflammatory and autoimmune conditions and is now in phase III trials to treat perianal fistulising Crohn disease 3. She highlighted how the safety and tolerability of the treatment were assessed in pre-clinical development and compliance with Good Manufacturing Practices (GMP) in their facility in Madrid. GMP can present particular challenges in regenerative medicine, as standards are defined 2 Allogenic stem cells are those derived from another human, as opposed to autologous stem cells, which are derived from the patient s own tissue. Adipose-derived stem cells are derived from fatty tissue. 3 A perianal fistula is a small channel between the end of the bowel and the skin near the anus, which usually develops after an anal abscess. 4

5 according to production practices of small molecule and biological pharmaceuticals. She added that the clinical trial approval was obtained in the first country in 90 days, half the time it usually takes for Advanced Therapy Medicinal Products (ATMPs) of 180 days. The product earned its orphan drug designation in 150 days. In fostering the development of this treatment, firstly, the interest of investigators and the proactive nature of the patients were essential to the successful launch of the trials. Secondly, TiGenix intensively developed the product specialist role for those administering the treatment. Through the various steps of its clinical development, the product has enjoyed the cooperation of multidisciplinary stakeholders and is on course for application to the EMA in The advent of virtual trials Dr Miguel Orri, Senior Director for Clinical Sciences, Pfizer Dr Orri outlined some significant pressures that have given rise to the demand for virtual trials: As a result of the increasing demand in the development of new products to demonstrate safety and effectiveness, sponsors require more data to gain approval of a medicine, and in so doing often make clinical trials more burdensome to the trial participants. Patients and prospective trial participants often do not have access to relevant investigators, which both deprives patients from the most advanced therapies and hinders recruitment leading to delays in the start and finish of a trial and eventually to new medicines reaching patients. Administrative requirements and the demands on study personnel create a discrepancy between the resources used for the conduct of clinical trials and their viability in an academic setting. He outlined the development of the world s first fully virtual clinical trial, conducted by Pfizer in featuring recruitment by social media, and continued to highlight some of the key changes that may occur as such trials become more widespread: Clinical trials can be redesigned to promote greater engagement with patients: engaged patients are likely to provide better data. Pfizer s REMOTE trial has demonstrated that it is possible for patient s identity to be verified and informed consent to be appropriately given remotely. Data collection directly from the patient will provide for real time data collection and remote monitoring. This will allow investigators and sponsors access to patient data and safety signals in real time. The primary care physician can currently be a barrier to patient participation in trials, as referrals mean they lose the patient to the investigator and at the end of the trial often do not know what treatment their patient received and what outcome was achieved. Virtual trials can keep the primary care physician engaged: she or he remains the treating physician. Patients can more easily be given their clinical trial data at the end of the trial, which may be integrated into their (electronic) medical records. Regulating the trials of the future Anastassia Negrouk, Head of International Regulatory & Intergroup Unit, European Organisation for Research & Treatment of Cancer (EORTC) 5

6 Ms Negrouk gave a brief overview of EORTC, highlighting its strong advocacy on the use of personalised medicines to fight cancer. She argued that personalised medicines will ensure the best survival rate whilst offering potential for cost savings. Ms Negrouk introduced the EORTC screening platform which features 18 screening centres in 10 EU member states and tests tissues for different biomarkers. Patients that agree to transfer their clinical data are screened for biomarkers, which can then be used for identifying clinical trials relevance for these patients (either from EORTC s database of active trials or from other academic and commercial sponsors). This inverts the traditional recruitment paradigm, which depends on contact with an investigator working on a specific trial. Regarding the Commission s proposal, Ms Negrouk welcomed specific features introduced into the proposed text, which would allow for an efficient EORTC clinical trials platform, including centralisation of clinical trial procedures via the proposed e-portal, sponsors being allowed to suggest reporting member states, and a risk-based approach that will allow appropriate and proportionate trial management. However, according to Ms Negrouk, questions still remained on the flexibility of the text to allow future mutual recognition between member states. Ms Negrouk further commented that trials for a new indication of a registered product should be considered low-risk, to favour the discovery of new treatments. With regard to cost-reduction and the future development of research, she called for the waiving of assessment fees for non-commercial research and the reimbursement of medicinal products used in a clinical trial if they are used according to their authorised indication or as per standard clinical practice. New models of pharmaceutical innovation Dr Richard Barker, Director at the Centre for the Advancement of Sustainable Medical Innovation (CASMI) Dr Barker focused on the important changes that may occur in the clinical environment in the coming 10 to 15 years. He noted that approximately 200bn is invested per year in the development of new medicines, resulting in around new treatments for the patient. This high cost must be explained and tackled. He identified three gaps that prevent clinical trials on innovative medicines from translating into authorised treatments: 1. Failure to translate bioscience breakthroughs into therapies ready for clinical trials. 2. Failure rate and cost of getting clinical candidates through to approval and use. 3. Failure of health systems and patients to adopt innovative treatments. Focusing on how to bridge the second gap, he claimed six transitions are necessary: 1. From a symptomatic to a molecular definition of disease, to identify the populations that will receive the most favourable benefit/risk ratio for a treatment. Certain groups of patients get greater benefit, or suffer reduced side effects: these must be analysed to discover genetic or other biological differences that distinguish these patients, and treat them accordingly. This stratified or personalised medicine requires diagnostics to identify the relevant biomarkers; these must be regulated together. Meanwhile, opportunities for retrospective analysis of trial data should be sought. 6

7 2. From reliance on randomised clinical trials (RCTs) to a mix of RCTs and real world data. Phase III trials will never be large enough to eliminate risk, are increasingly expensive, and usually necessarily work with unrepresentative populations. New technologies allow the accumulation of evidence in real world practice, e.g. electronic medical records, patient-reported outcomes of clinical trials, and remote monitoring devices to feed back treatment results automatically. 3. From a focus solely on efficacy and safety to defining the value of treatments - the development of such a focus requires the development of relevant comparators and the overhaul of pricing and reimbursement systems: prices may need to go up as well as down if a treatment proves effective. 4. From a labour-intensive analogue clinical trials data collection, with the expense and inconvenience of bringing patients to investigator sites, towards more cost-effective digital data-gathering, such as described by Dr Orri. 5. From a simple range of chemical drugs to a wide variety of therapeutic agents, as described by Dr Janssen. The nature of benefit and risk can vary widely between these therapies, resulting in challenges to traditional clinical trial design and assessment: there is a need for developers, regulators and payers to engage in a continuing dialogue to acknowledge the value of innovative treatments and provide for regulatory routes to bring the treatment to the patient. 6. From a one size fits all regulatory mentality to an adaptive approach, in which the development programme is designed on a medicine-specific basis. This could result, for example, in larger phase II trials in molecularly-defined populations paving the way for conditional approval (and thus reimbursement), with real world data monitoring to refine usage and assess value. Conditional approval is already available at the EMA but can be refined this is part of a wider discussion on adaptive licensing. Regarding the Commission s proposal, Dr Barker confirmed that it should not only try to address the deficiencies of the current Clinical Trials Directive, but also anticipate future trends in medical research and clinical development. Responses to issues raised by the panel Speakers in this session were asked to give a brief response to issues raised by the previous speakers. Dr Cornelius Schmaltz, Scientific and Policy Officer - Clinical Trials (F2), DG RTD, European Commission Dr Schmaltz presented DG RTD s interest in supporting trials: without ethically and scientifically sound trials, no new treatments would reach patients. He noted that DG RTD had worked closed with DG SANCO in the development of the new proposal, with the objective of raising the standards of research in Europe and making it welcoming for medical innovation and international cooperation. He outlined DG RTD s contribution to the funding of clinical trials via the FP7 Health Programme which has allocated more than 900 million to collaborative projects performing clinical trials. These range from early phase I trials of advanced-therapy medicinal products to large phase IV studies of comparative effectiveness of different authorised interventions but also include trials with medical devices and radiotherapy. In addition both the 7

8 European Developing Countries Clinical Trial Partnership (EDCTP) and the public-private partnership Innovative Medicine Initiative (IMI) contribute to the funding of clinical trials. He added that the planned new EU funding programme for research and innovation from 2014 to 2020, Horizon 2020, had not yet been decided upon by Council and Parliament, but that the Commission proposal as well as the initial comments of Council and Parliament on the legislative texts, again place a very strong emphasis on the validation of innovations through clinical trials. Dr Ingrid Klingmann, European Forum for Good Clinical Practice (EFGCP) Dr Klingmann briefly outlined the discussion at EFGCP s workshop on ethical assessment in the proposed Regulation of November 2012, with participation of ethics committees from 20 different countries. They sought: Mentioning of the role of ethics committees in the final Regulation text; Clarification on what an independent ethical review is specifically if this means the requirement that an ethics committee is not related to the involved hospital/institution; the need for longer dossier validation timelines to allow ethics committees a proper assessment of a requested lowinterventional clinical trial status; A need for clarification of the process of involvement of ethics committees in Part I and Part II assessments; Clarity on how the opinion of ethics committees from the reporting and all concerned member states will be reflected in the reporting member states assessment especially if an opinion is negative; Further clarification of the conditions for a waiver of patients informed consent in emergency situations; Reassurance on the functionality of the single assessment portal once the Regulation will come into force. Kaisa Immonen-Charalambous, Senior Policy Advisor, European Patients Forum (EPF) Ms Immonen-Charamboulos called for a greater involvement of patients in clinical trials. Article 9 of the proposed Regulation, on seeking patient perspectives in assessment, is a positive development, but should be strengthened. EPF will shortly release their position paper outlining how this can happen. Meanwhile, with the advances in therapies, virtual trials and adaptive licensing identified by the speakers, patients need to be better informed on trials in order to promote involvement and guarantee meaningful informed consent. Innovative approaches to this, such as outlined by Dr Orri, should be further explored. Ms Immonen-Charalambous also noted the EUPATI project, part of the Innovative Medicines Initiative partnership between the European Commission and pharmaceutical association EFPIA, which will develop a number of resources supporting patients and citizens to become effective advocates and partners in medicines development. Dr Greet Musch, Director General, Belgian Federal Agency for Medicines and Health Products (FAMHP) Dr Musch welcomed the new proposal, adding that was an opportunity to increase the number, and enhance the standard, of clinical trials in Europe. She called for ethical and scientific reviews of clinical trials to be run simultaneously and called for the inclusion of ethics committees in Part I assessments of clinical 8

9 trials. Dr Musch stated that the proposal is an opportunity for national competent authorities and ethics committees to reorganise themselves to be responsible for trials hand in hand. The timelines proposed are challenging, but necessary to keep clinical research in the EU and provide early access to treatments for patients. Dr Musch also stressed the importance of building trust between member states in the field of clinical trial assessment. She welcomed the involvement of patients as well as the introduction of a risk-based approach, as it would allow adapted timelines for products that do not need specific monitoring. Subsequently, it would decrease the administrative burden on sponsors and regulators. However, she noted that the low level of recruitment of trial participants is a challenge to the conduct of clinical trials. Member states should consider how to address this together. Dr Musch also noted that one of the current text s strengths is its respect for Good Clinical Practice (GCP) and Good anything Practice (GxP), which demands thorough inspections, both in the EU and worldwide. Flaminia Macchia, EU Public Affairs Director, EURORDIS Ms Macchia argued that the Commission proposal currently did not take into account issues related to clinical trials in rare diseases, which are always multicentre and multinational and for which expertise is scarce. She announced that EURORDIS would seek an amendment of the Part II assessment (Art. 7bis) and would try to create a dialogue procedure between the relevant EMA Scientific Expert Groups and the reporting member state in cases where a clinical trial is conducted in the field of rare diseases. This amendment would aim to collect the most up-to-date and accurate knowledge and expertise at EU level to assess the suitability of the research protocol for the rare disease concerned. She also noted her interest in the idea of adaptive licensing described by Dr Barker, and noted that concepts of science and ethics cannot be separated. Nick Sykes, Senior Director, Worldwide Regulatory Strategy, Pfizer Mr Sykes focused on the suitability of the current proposal with regard to the types of future development presented: the proposed Regulation does not hinder them, but could be more supportive. Coordinated assessment will depend to a large degree on the pragmatism of the member states involved something that cannot be guaranteed. Meanwhile, a review clause should be included to help future proof the legislation by mandating an assessment, and if necessary a review of the legislation, five years after the Regulation s entry into force. Dr Beth Thompson, Policy Advisor, Wellcome Trust Dr Thompson briefly outlined the Wellcome Trust and its activities as a major not-for-profit research funding organisation. She broadly welcomed the Commission s proposal, including the introduction of a risk-adapted approach. She outlined two areas of clinical research that had not been addressed by the speakers: trials on older drugs (important to understand comparative benefit/risk and investigate new indications), and the use of vitamin and nutritional supplements: as these are not usually considered as medicines, there are issues with compliance with Good Manufacturing Practices that are designed for pharmaceuticals. 9

10 She also placed the future of clinical trials in the wider regulatory context. In particular, the current exceptions to health research in the proposed Data Protection Regulation may be endangered in the European Parliament by the rapporteur and lead committee, LIBE: the removal of these exceptions could have significant consequences on conducting clinical research in Europe and on the outcome of the Clinical Trials Regulation. Debate and concluding remarks The floor was then opened for a discussion between the audience, the speakers and the respondents. In response to comments by other speakers and respondents on the Commission s proposal, Mr Soro replied: To Dr Klingmann s question, he agreed that an ethics committee is expected to be independent of the investigators institution. Regarding the issue of the ethical committees, he noted that they are not specifically mentioned in the proposed text because it would be up to the member states to organise how reviews are shared between national competent authorities and ethics committees. This does not mean that ethics committees have been bypassed. He confirmed that he would stand by the Commission s proposal on emergency trials. On rare diseases, he stated that no specific paragraph was added because the Regulation should give a framework for clinical trials in general, and not for specific trials. Concerning a review clause, he expressed doubts that the Commission would be able to produce a meaningful assessment five years after its entry into force, as this would be too short a period to judge. For Mr Soro, the Commission would rather adapt to changes by pushing the ad hoc revision of the Regulation or the creation of a new one. He further announced he had been in discussions with the Data Protection Supervisor regarding the need for exceptions in the field of health research in the Data Protection Regulation, and confirmed Dr Thompson s earlier comments. In reaction to Mr Soro s comments: Ms Macchia reacted to Mr Soro s remarks regarding the absence of a specific chapter on rare diseases by highlighting the legal basis for rare diseases in the orphan medicinal products legislation and that the Clinical Trials Regulation would be a good opportunity to create a specific mechanism for these diseases. Dr Barker added that the proposal should have a review mechanism, given the fast pace of change in clinical trials development as outlined in the day s discussions. In reply, Mr Soro highlighted that the Regulation would at least prevent member states from adopting implementing measures that do not correspond to the Commission s final text and insisted that the Commission is unlikely to draft a review of its proposal in the coming years. 10

11 Other speakers also responded to issues that had been raised over the course of the discussion: Ms Negrouk highlighted the high costs of clinical trials in the field of rare diseases at a global level and therefore the gathering and transfer of data is an issue. In order to scale down costs, she suggested grouping tested population by biomarkers. She also agreed with the course of action chosen by the Commission to design a single contact point for registration of clinical trials. Mr Sykes emphasised the need to find a balance between the flexibility of the new Regulation and legal certainty to be able to face the upcoming challenges in conducting clinical trials. He further suggested that, whether to address issues of patient availability, investigator engagement, or costs, in future the investigator could be based in another member state than that of the patient. Therefore important to put in place mutual recognition mechanisms to grant the authorisation of such clinical trials in the investigator s and patients member state, to facilitate such trials. Mr Pim de Boer, representing the European Federation of Asthma and Allergy Associations (EFA), introduced the audience to the manner in which his organisation involves patients in the design of their own clinical trials. He noted that these patients have a constant dialogue with the sponsors and have the possibility to rule out specific tests as well as include others. Ms Immonen-Charamboulos advocated for actions to increase awareness by the public on clinical trials. Furthermore, the Commission would have to ensure that it has a strong understanding and inclusion of health literacy, the understanding and awareness of new issues in the health sector, and in the conduct of clinical trials. She called for an EU Strategy on health-related issues. Closing remarks by Ms Rebecca Taylor MEP In closing the event, Ms Taylor confirmed that clinical trials have become more complex as new therapies emerged. To Ms Taylor, these challenges call for an overhaul of the clinical trials paradigm, where the role of the patients should develop towards greater involvement. The role of ethics committees will remain important: their inclusion in the final text should be clear but there may be a need for streamlining to meet the competitive timelines that Europe needs. Ms Taylor also welcomed the risk-based approach. After agreeing on the need for a wider public education on clinical trials, she repeated her optimism in getting the proposal approve swiftly given its broad approval thus far. 11